We performed global gene expression profiling to complement the ongoing positional cloning effort to identify susceptibility genes for diabetes and its predictors, insulin resistance and obesity. To this end, we have examined skeletal muscle gene expression profiles in non-diabetic full-blooded Pima Indians using 1) human oligonucleotide microarrays containing 6800 genes and 35000 expressed sequence tags (ESTs) and 2) differential display PCR, followed by Real Time RT-PCR. This work has been published in Diabetologia, DOI 10.1007/s00125-002-0905-7. The potential roles of the differentially expressed genes/ESTs in insulin resistance are evaluated by examining 1) their functions in relevant metabolic pathways, such as IRS-1 (Diabetes 51, Supplement 2: A266) and 2) their chromosomal locations relative to peaks of linkage to insulin action and diabetes in a genome-wide scan in the Pima population, such as ORP150 (Diabetes 51:1618-1621). We will also use primary human skeletal muscle culture system to identify potentially novel members of insulin signaling pathway and to compare the gene profiles between human muscle biopsies and cultured muscle cells from the same donors. To identify susceptibility genes for obesity, we have performed a gene expression profiling experiment using freshly isolated adipocytes from 20 lean and 19 obese Pima Indians. We are currently analyzing the data, and will pursue potential susceptibility genes for obesity based on functions and chromosomal locations with linkage to obesity measures.